1. Field of the Invention
The present invention relates to processes for the preparation of compounds of formula (IA):
Such compounds are useful for prevention and/or treatment of neurodegenerative diseases such as Alzheimer's disease.
2. Discussion of the Background
Alzheimer's disease is a neurodegenerative disorder characterized from a histopathologic point of view by a diffuse presence of extracellular and perivascular neuritic plaques and intracellular neurofibrillary tangles in the cerebral parenchyma of Alzheimer patients. Neuritic plaques are mainly composed of aggregates of a protein with 39-43 amino acid residues known as β-amyloid (βA), and, depending on the numbers of amino acids, Aβ39, Aβ40, Aβ42 and Aβ43.
Compounds have been reported which can reduce the production of the most neurotoxic isoform of β-amyloid, namely the form containing 42 amino acids (Aβ42), through their interaction with a macromolecular/multiprotein enzymatic complex with aspartyl-protease activity, known as γ-secretase.
WO 2004/074232 discloses derivatives of 1-(2-halobiphenyl-4-yl)-cyclopropanecarboxylic acid of formula (I) capable of modulating γ-secretase activity without affecting other important metabolic processes such as cyclooxygenase-enzymes activity.
R is defined below, and X is preferably fluorine.
The key intermediate step in the preparation of said compounds is a Suzuki reaction between a suitable phenylboronic acid or an ester thereof with a 3,4-dihalo-cyclopropanecarboxylic acid, preferably a 3-fluoro-4-halo-cyclopropanecarboxylic acid.
In WO 2004/074232, 3-fluoro-4-halo-cyclopropanecarboxylic acid may be obtained starting from 3-fluoro-4-halo-toluene which is transformed into the corresponding benzyl bromide by radical bromination in carbon tetrachloride (CCl4); the resulting bromide is then transformed into the 3-fluoro-4-halophenylacetonitrile; and the latter is reacted with 1,2-dibromoethane to give the corresponding 3-fluoro-4-halo-phenylcyclopropanenitrile, which is finally hydrolyzed to the desired 3-fluoro-4-halo-cyclopropanecarboxylic.
However, the process described in WO 2004/074232 provides a low overall yield (12-14%) and suffers from severe restrictions for the industrial use. In particular, the final Suzuki coupling reaction has a poor yield, and the resulting product is difficult to purify by crystallization without a loss of yield. Silica gel chromatography has been used for such purification, but the scale-up of silica gel chromatography is tedious and requires large volumes of solvents.
Moreover, the radical bromination step used for the preparation of the benzyl bromide derivative gives a significant amount of the bis-halogenated side-product, detrimental to its yield, and involves the use of CCl4 which is highly toxic and also both ozone-depleting and a greenhouse gas.
Thus, there remains a need for a process for producing such compounds which does not suffer from the above-mentioned drawbacks.